2-aryl-acetic acids, their derivatives and pharmaceutical compositions containing them

ABSTRACT

Selected 2-arylacetic acids, their derivatives and pharmaceutical compositions that contain these compounds are useful in inhibiting chemotactic activation of neutrophils (PMN leukocytes) induced by the interaction of Interleukin-8 (IL-8) with CXCR1 and CXCR2 membrane receptors. The compounds are used for the prevention and treatment of pathologies deriving from said activation. In particular, 2(ortho)-substituted arylacetic acids or their derivatives, such as amides and sulfonamides, lack cyclo-oxygenase inhibition activity and are particularly useful in the treatment of neutrophil-dependent pathologies such as psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to 2-arylacetic acids and derivativesthereof, and to pharmaceutical compositions containing them, which areused in the prevention and treatment of tissue damage due to theexacerbated recruitment of polymorphonucleated neutrophils (PMNleukocytes) at inflammation sites. In particular, the invention isdirected to 2-phenylacetic acids and derivatives thereof for thetreatment of IL-8 mediated diseases, such as psoriasis, ulcerativecolitis, COPD and of the damages caused by ischemia and reperfusion.

BACKGROUND OF THE INVENTION

Particular blood cells (macrophages, granulocytes, neutrophils,polymorphonucleated) respond to a chemical stimulus (when stimulated bysubstances called chemokines) by migrating along the concentrationgradient of the stimulating agent, through a process called chemotaxis.The main known stimulating agents or chemokines are represented by thebreakdown products of complement C5a, some N-formyl peptides generatedfrom lysis of the bacterial surface or peptides of synthetic origin,such as formyl-methionyl-leucyl-phenylalanine (f-MLP) and mainly by avariety of cytokines, including Interleukin-8 (IL-8, also referred to asCXCL8). Interleukin-8 is an endogenous chemotactic factor produced bymost nucleated cells such as fibroblasts and macrophages.

In some pathological conditions, marked by exacerbated recruitment ofneutrophils, a more severe tissue damage at the site is associated withthe infiltration of neutrophilic cells. Recently, the role ofneutrophilic activation in the determination of damage associated withpost ischemia reperfusion and pulmonary hyperoxia was widelydemonstrated.

The biological activity of IL-8 is mediated by the interaction of theinterleukin with CXCR1 and CXCR2 membrane receptors which belong to thefamily of seven transmembrane receptors, expressed on the surface ofhuman neutrophils and of certain types of T-cells (L. Xu et al., J.Leukocyte Biol., 57, 335, 1995). Selective ligand are known which candistinguish between CXCR1 and CXCR2: GRO-α is an example of a CXCR2selective chemotactic factor.

Potential pathogenic role of IL-8 in pulmonary diseases (lung injury,acute respiratory distress syndrome, asthma, chronic lung inflammation,and cystic fibrosis) and, specifically, in the pathogenesis of COPD(chronic obstructive pulmonary disease) through the CXCR2 receptorpathway has been widely described (D. W P Hay and H. M. Sarau., CurrentOpinion in Pharmacology 2001, 1:242-247).

Characteristic neutrophil accumulation occurs in acute and chronicpathologic conditions, for example in the highly inflamed andtherapeutically recalcitrant areas of psoriatic lesions. Neutrophils arechemotactically attracted and activated by the sinergistic action ofchemokines, IL-8 and Gro-a released by the stimulated keratinocytes, aswell as of the C5a/C5a-desArg fraction produced via the alternativecomplement pathway activation (T. Terui et al., Exp. Dermatol., 9, 1,2000).

Novel classes of potent and selective inhibitors of IL-8 biologicalactivities (R-2-arylpropionic acid amides and N-acylsulfonamides) havebeen described as effective inhibitors of IL-8 induced neutrophilschemotaxis and degranulation (WO 01/58852; WO 00/24710). Furthermore,novel subclasses of R and S 2-phenylpropionic acids have been described(WO 03/043625) as potent IL-8 inhibitors completely lacking theundesired cyclo-oxygenase enzyme (COX) inhibitory effect. The inhibitionof prostaglandin synthesis deriving from COX inhibition involves, infact, an increase of cytokine production which results in theamplification of the undesired pro-inflammatory effects of neutrophils.

DETAILED DESCRIPTION OF THE INVENTION

Medicinal Chemistry studies have shown the crucial role of the methylgroup on the propionic chain of 2-arylpropionic acids in order for themto exert their IL-8 inhibitory activity.

We have, in fact, found that 2-[4-isobutylphenyl]acetic acid (ibufenac)and 2-[3-benzoylphenyl]acetic acid (ketofenac), well known COXinhibitors belonging to the family of phenylacetic acids, do not exertany IL-8 inhibitory activity which is present, instead, in the potentcorresponding phenylpropionic acids, such as ibuprofen and ketoprofen.

In general, 2-phenylacetic acids and their derivatives, such as amidesand sulfonamides, lack any IL-8 inhibitory activity and this confirmsthe crucial role of the methyl group in the corresponding2-phenylpropionic derivatives.

We have completed SAR studies on the different classes of2-arylpropionic acids and derivatives described above, which allowed toexactly clarify the pharmacophore structure shared by all these novelclasses of IL-8 inhibitors.

A pharmacophore is defined as the ensemble of steric and electronicrequirements, in a class of biologically active compounds, necessary toensure the biological activity; in general, the pharmacophore can beconsidered the ensemble of steric and electronic requirements necessaryto ensure positive interactions between a biologically active moleculeand its target. The assumption, in a pharmacophore study, is that allcompounds in a training set share the same mechanism and interact withthe same biological target.

We have now defined two pharmacophore models: a first model accountingfor the biological activity of IL-8 inhibitors selectively acting onCXCR1 mediated pathway (hereinafter CXCR1 inhibitors), and a secondmodel representing the sterile and electronic requirements of the IL-8inhibitors dually acting on CXCR1 and CXCR2 mediated pathway(hereinafter CXCR1/CXCR2 inhibitors). These two models account for theobserved Structure Activity Relationships since all the inactivemolecules tested against the two complete pharmacophore hypothesiseither miss crucial features superimposition (unfit) or fit thepharmacophore hypothesis in a high energy conformations. The two newlyfound pharmacophore models share four out of respectively five and sixfeatures; these four features are completely superimposable in the 3Dchemical space. An outline of the common portion of the pharmacophoremodels is illustrated in FIG. 1.

DESCRIPTION OF THE FIGURES

FIG. 1 graphically shows the four common features of the pharmacophoresof respectively CXCR1 inhibitors and CXCR1/CXCR2 inhibitors. Thefollowing features types take part in the pharmacophore portion: twoHydrogen Bond Acceptors, one Hydrophobic Aromatic and one HydrophobicAliphatic. The (aromatic and aliphatic) hydrophobic features arerepresented by spheres of 1.7 Angstroms radius. The hydrogen bondacceptor is represented by a vector function consisting two sphereswhose centroids are 3.0 Angstroms apart. The smaller (1.7 Angstromsradius) sphere defines the position of the hydrogen bond acceptor atomon the ligand and the larger sphere (23 Angstroms) defines the projectedpoint of the hydrogen bond acceptor from the receptor site. The solidsphere represents the exact location in the 3D space of the methyl groupof the phenylpropionic moiety.

FIG. 2 illustrates superimposition of the following Arylpropionicderivatives: R(−) 2-(4-isobutylphenyl) propionic acid;R(−)-2-(4-isobutylphenyl)propionyl methanesulphonamide;R(−)-N-(2′-hydroxyethoxyethyl)-2-(4-isobutylphenyl)propionamide. Thesolid sphere represents the exact location in the 3D space of the methylgroup of the phenylpropionic moiety.

FIG. 3 illustrates superimposition of the following Arylaceticderivatives: (2-methyl-4-isobutylphenyl)acetic acid;(2-methyl-4-isobutylphenyl)acetyl methanesulphonamide;(2-methyl-4-isobutylphenyl)acetamide.

FIG. 4 illustrates superimposition of the following Arylaceticderivatives: (5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid;(1-benzoyl-2-methyl-1H-indol-3-yl)acetyl methanesulphonamide;(2-chloro-3-benzoylphenyl)acetamide.

Pharmacophore generation has been performed using the Catalyst™software, version 4.7 (Molecular Simulations, Inc., San Diego, Calif.),which is designed to identify common configurations of the activemolecules by means of their chemical features. A configuration is a setof relative locations in 3D space, each associated with a feature type.All the compounds in the training set were described in terms of theirchemical functions associated within the 3D space. Furthermore, eachchemical moiety can be considered by the software as more than onefeature on the basis of the found similarity. For example, an aromaticring can “establish” both hydrophobic interactions and π-π interactionsin the target site and this different behaviour is referred to differentfeatures (Hydrophobic, Hydrophobic aromatic).

A functional group in a molecule can be associated to more than onefeature, depending on its chemical and phisical properties, anddifferent functional groups can show behaviour similarity in theinteraction with the target so mapping the same feature.

Analysis of the feature definitions and selection of the features is acrucial step in the pharmacophore hypothesis generation. It is wellknown that the most important forces involved in molecular recognitionare represented by electrostatic interactions, hydrogen bonding andhydrophobic interactions. We adopted several features definitionsrelating the chemical nature of the group to the ability of engagingspecific interactions responsible for the biological activity.

Features Definitions

Hydrogen Bond Acceptor (HBA) (Lipid)

A Hydrogen bond acceptor lipid feature matches the following types ofatoms or groups of atoms which are surface accessibility: nitrogens,oxygens, or sulphurs (except hypervalent) that have a lone pair andcharge less than or equal to zero. Since a lipid environment wasconsidered, all basic amines (primary, secondary and tertiary) areincluded in this definition. The hydrogen bond is a highly directionalinteraction, this feature is so indirectly linked to the theoricposition of the corresponding hydrogen donor. Three hydrogen bondspositions are for instance considered on carbonyl group (acceptor), thefirst two along the ideal positions of the lone pairs and a third onealong the C═O bond direction.

Hydrophobic (Aliphatic, Aromatic)

Hydrophobic feature is defined as a contiguous set of atoms that are notadjacent to any concentrations of charge (charged atoms orelectronegative atoms), in a conformer such that the atoms have surfaceaccessibility, including phenyl, cycloalkyl, isopropyl, and methyl.

Nevertheless it has been necessary to distinguish the aromatichydrophobic feature from the aliphatic one in order to grant a goodfitting with biological results. The former considers only the aromaticatoms, the latter considers only the aliphatic atoms.

A molecule is considered matching a configuration only if possesses aset of relative features and specific conformation such that itsfeatures can be superimposed with the corresponding “ideal” locations. Aset of features can be considered superimposed if each feature lieswithin a specific distance on tolerance, from the ideal point.

The absolute sphere centroids co-ordinates of each feature are listedbelow:

HYDROPHOBIC AROMATIC has Cartesian co-ordinates +2.588, +0.613, −1.940respectively along XYZ axes.

HYDROPHOBIC ALIFATIC has Cartesian co-ordinates of +1.788, +2.693,+1.260 respectively along XYZ axes.

HYDROGEN BOND ACCEPTOR PROJECTED POINT 1 has Cartesian co-ordinates of−2.713, +2.333, +2.840 respectively along XYZ axes.

HYDROGEN BOND ACCEPTOR ORIGIN 1 has Cartesian co-ordinates of −0.233,+0.936, +1.877 respectively along XYZ axes.

HYDROGEN BOND PROJECTED ACCEPTOR POINT 2 (optional) has Cartesianco-ordinates of −5.013, −1.188, −0.400 respectively along XYZ axes.

HYDROGEN BOND ACCEPTOR ORIGIN 2 (optional) has Cartesian co-ordinates of−2.688, −1.514, +1.472 respectively along XYZ axes.

Mapping of the first three features (HYDROPHOBIC ALIPHATIC, HYDROPHOBICAROMATIC, HYDROGEN BOND ACCEPTOR 1) is crucial for the biological IL-8inhibitory activity of the class; the fourth feature (HYDROGEN BONDACCEPTOR 2) can be optionally mapped by the molecules of the class butthe presence of the second hydrogen bond acceptor group is notindispensable.

Tolerances on all the distances between the chemical features have beenestablished in +0.5 Angstroms and tolerances on the geometric angles ±20degrees.

As previously discussed, other pharmacophore points are required inorder to complete the pharmacophore analysis but their description isnot relevant for the purposes of present invention. The observedCXCR1/CXCR2 selectivity in the class is strictly related to the abilityof the inhibitors to match specific points in the non-common part of thepharmacophore.

On the contrary, as far as the common part of the pharmacophore isconcerned, a general superimposition mode is observed for CXCR1inhibitors and CXCR1/CXCR2 inhibitors belonging to the classes of2-phenylpropionic acids, 2-phenylpropionyl sulphonamides and2-phenylpropionamides as outlined in FIG. 2. The solid sphere representsthe exact location in the 3D space of the methyl group of thephenylpropionic moiety.

In the retrieved ligands which partially or fully map this hypothesis(FIG. 2) the phenyl residue of the 2-phenylpropionic chemical structurealways matches very well the HYDROPHOBIC AROMATIC feature; the HYDROGENBOND ACCEPTOR (HBA) 1 feature is consistently well matched by thecarbonylic oxygen of the propionyl residue; the HYDROGEN BOND ACCEPTOR(HBA) 2 feature can be optionally matched by a second Hydrogen BondAcceptor atom on the residue linked at the amidic or sulphonamidicnitrogen; the HYDROPHOBIC ALIPHATIC feature is invariably matched by themethyl group of the propionyl residue. Phenylacetic acids andderivatives, on the basis of the above considerations, obviously fail tomatch the pharmacophore hypothesis, since the crucial HYDROPHOBICALIPHATIC feature, represented by the solid sphere in FIG. 2, is missingin their chemical structure.

We have now found out that selected subclasses of 2-arylacetic acids andderivatives thereof, which lack the methyl group of the propionylresidue, show the surprising ability to effectively inhibit IL-8 inducedneutrophils chemotaxis and degranulation.

The present invention thus provides use of 2-arylacetic acid compoundsand derivatives of formula (I):

and pharmaceutically acceptable salts thereof,

-   -   wherein    -   A includes the X atom and represents a 5-6 membered aromatic or        heteroaromatic ring optionally including a heteroatom, or a        further heteroatom when X is N, selected from N (nitrogen), O        (oxygen), S (sulfur); the 5-6 membered aromatic or        heteroaromatic ring is optionally fused with a second ring to        give bicyclic aromatic or heteroaromatic structures;    -   labels 1 and 2 mark the relevant positions on the A ring;    -   the X atom is selected from N (nitrogen) and C (carbon);    -   R is a substituting group on the A ring selected from:        -   a group in the 3 (meta) position selected from a linear or            branched C₁-C₅ alkyl, C₂ C₅-alkenyl or C₂-C₅-alkynyl group,            substituted or not-substituted phenyl, linear or branched            C₁-C₅ hydroxyalkyl, C₂-C₅-acyl, substituted or            not-substituted benzoyl;        -   a group in the 4 (para) position selected from C₁-C₅ alkyl,            C₂-C₅-alkenyl or C₂-C₅-alkynyl group, C₃-C₆-cycloalkyl,            C₁-C₅-acyloxy, substituted or not-substituted benzoyloxy,            C₁-C₅-acylamino, substituted or not-substituted            benzoylamino, C₁-C₅-sulfonyloxy, substituted or            not-substituted benzenesulfonyloxy,            C₁-C₅-alkanesulfonylamino, substituted or not-substituted            benzenesulfonylamino, C₁-C₅-alkanesulfonylmethyl,            substituted or not-substituted benzenesulfonylmethyl,            2-furyl; 3-tetrahydrofuryl; 2 thiophenyl;            2-tetrahydrothiophenyl groups or a C₁-C₈-alkanoyl,            cycloalkanoyl or arylalkanoyl-C₁-C₅-alkylamino group;    -   Hy is a small hydrophobic group with a steric hindrance factor ν        ranging between 0.5 and 0.9 Å (where ν is the Charton steric        constant for substituents), including methyl, ethyl, chlorine,        bromine, methoxy, trifluoromethyl;    -   The Y group is selected from O (oxygen) and NH;    -   when Y is O (oxygen), R′ is H (hydrogen);    -   When Y is NH, R′ is selected from        -   —H, C₁-C₅-alkyl, C₁-C₅-cycloalkyl, C₁-C₅-alkenyl;        -   an amino acid residue consisting of straight or branched            C₁-C₆-alkyl, C₁-C₆-cycloalkyl, C₁-C₆-alkenyl, phenylalkyl            substituted with one or more carboxy (COOH) groups;        -   an amino acid residue consisting of straight or branched            C₁-C₆-alkyl, C₁-C₆-cycloalkyl, C₁-C₆-alkenyl, phenylalkyl,            bearing along the chain a heteroatom selected from oxygen            and sulfur and with one or more carboxy (COOH) groups;        -   a residue of formula —CH₂—CH₂—Z—(CH₂—CH₂O)nR″ wherein R″ is            H or C₁-C₅-alkyl, n is an integer from 0 to 2 and Z is            oxygen or sulfur;        -   a residue of formula —(CH₂)n-NRaRb wherein n is an integer            from 0 to 5 and each Ra and Rb, which may be the same or            different, are C₁-C₆-alkyl, C₁-C₆-alkenyl or, alternatively,            Ra and Rb, together with the nitrogen atom to which they are            bound, form a heterocycle from 3 to 7 members of formula            (II)

-   -   -   wherein W represents a single bond, CH₂, O, S or N—Rc,            wherein Rc is H, C₁-C₆-alkyl or C₁-C₆-alkylphenyl;        -   a residue OR″ wherein R″ is H, methyl, carboxymethyl;

    -   a residue of formula SO₂Rd wherein Rd is C₁-C₆-alkyl,        C₁-C₆-cycloalkyl, C₁-C₆-alkenyl;

    -   in the preparation of a medicament for the inhibition of IL-8        induced human PMNs chemotaxis.

The aromatic ring in the A group may be optionally substituted withfurther groups such as C₁-C₅-alkyl or a halogen group.

The term “substituted” in the above definition means substituted with agroup selected from C₁-C₅-alkyl, halogen, hydroxy, C₁-C₅-alkoxy, amino,C₁-C₅-alkylamino, nitro, or a cyano group.

Preferred A groups in compounds of formula (I) are aromatic orheteroaromatic rings selected from benzene, naphthalene, pyridine,pyrimidine, pyrrole, imidazole, furane, thiophene, indole and7-aza-indole.

Preferred compounds of formula (I) are those wherein the group YR′ isOH; preferred R′ groups when Y is NH are:

-   -   the amino acid residue of glycine, β-alanine, γ-aminobutyric        acid or residues of an L-α-amino acid selected in the group of        L-alanine, valine, leucine, isoleucine, nor-leucine,        phenylalanine, S-methylcysteine, methionine;    -   a residue of formula —CH₂—CH₂—O—(CH₂—CH₂O)R″ wherein R″ is H or        C₁-C₅-alkyl;    -   a residue of formula —(CH2)n-NRaRb wherein n is an integer from        2 to three, more preferably 3 and the group NRaRb is        N,N-dimethylamine, N,N-diethylamine, 1-piperidyl, 4-morpholyl,        1-pyrrolidyl, 1-piperazinyl, 1-(4-methyl)piperazinyl;    -   a residue OR′ wherein R′ is H, methyl;        a residue of formula SO₂Rd wherein Rd is methyl, ethyl or        isopropyl.

Preferred R groups in compounds of formula (I) are 3′-benzoyl,3′-(4-chloro-benzoyl), 3′-(4-methyl-benzoyl), 3′-acetyl, 3′-propionyl,3′-isobutanoyl, 3′-ethyl, 3′-isopropyl, 4′-isobutyl,4′-trifluoromethanesulphonyloxy, 4′-benzenesulphonyloxy,4′-trifluoromethanesulphonylamino, 4′-benzenesulphonylamino,4′-benzenesulphonylmethyl, 4′-acetyloxy, 4′-propionyloxy, 4′-benzoyloxy,4′-acetylamino, 4′-propionylamino, 4′-benzoylamino.

Preferred Hy groups in compounds of formula (I) are methyl, ethyl,chlorine, bromine, methoxy, trifluoromethyl.

Particularly preferred is the use of compounds selected from:

-   (3-benzoyl-2-methylphenyl)acetic acid-   (2-chloro-3-propionylphenyl)acetic acid-   (3-isopropyl-2-methylphenyl)acetic acid-   (4-isobutyl-2-methylphenyl)acetic acid-   {2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid-   {2-methyl-4-[(trifluoromethanesulphonyl)amino]phenyl}acetic acid-   {2-chloro-4-[(trifluoromethanesulphonyl)oxy]phenyl}acetic acid-   (5-acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid-   [1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid-   (5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid-   [1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]acetic acid-   (5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid-   (1-benzoyl-2-methyl-1H-pyrrol-3-yl)acetic acid-   (1-benzoyl-2-chloro-1H-pyrrol-3-yl)acetic acid-   (1-benzoyl-2-methyl-1H-indol-3-yl)acetic acid-   [1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetic acid-   (1-isopropyl-2-methyl-1H-pyrrole[2,3-b]pyridin-3-yl)acetic acid-   (3-benzoyl-2-methoxyphenyl)acetic acid-   (5-acetyl-1-methyl-1H-pyrrol-2-yl)acetamide-   (5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-carboxymethylacetamide-   (S)(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxyethyl)acetamide-   (5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(3-dimethylaminopropyl)acetamide-   (S)(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(1-carboxy-2-methoxyethyl)acetamide-   (4-isobutyl-2-methylphenyl)acetamide-   (2-chloro-3-propionylphenyl)-N-(3-dimethylaminoethyl)acetamide-   (3-isopropyl-2-methylphenyl)-N-[3-(1-piperidinyl)propyl]acetamide-   (3-benzoyl-2-methylphenyl)acetamide-   (1-benzoyl-2-methyl-1H-indol-3-yl)acetamide-   (1-benzoyl-2-methyl-1H-indol-3-yl)-N-(3-dimethylaminopropyl)acetamide-   [1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetamide-   [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide-   {2-chloro-4-[(trifluoromethanesulphonyl)oxy]phenyl}-N-(2-hydroxyethoxyethyl)acetamide-   (1-benzoyl-2-methyl-1H-pyrrol-3-yl)-N-(2-methoxyethyl)acetamide-   (1-benzoyl-2-chloro-1H-pyrrol-3-yl)-N-[3-(1-morpholino)propyl]acetamide-   (5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetamide-   (5-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxymethyl)acetamide-   [1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]-N-(2-hydroxyethoxyethyl)acetamide-   [1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]acetamide-   {2-methyl-4-[(phenylsulphonyl)amino]phenyl}-N-(3-dimethylaminopropyl)acetamide-   (3-benzoyl-2-methoxyphenyl)acetamide.

The present invention further provides novel 2-arylacetic acids andderivatives of formula (Ia),

and pharmaceutically acceptable salts thereof,wherein:A includes the X atom and represents a 5-6 membered aromatic orheteroaromatic ring optionally including a heteroatom, or a furtherheteroatom when X is N, selected from N (nitrogen), O (oxygen), S(sulfur); the 5-6 membered aromatic or heteroaromatic ring is optionallyfused with a second ring to give bicyclic aromatic or heteroaromaticstructures;labels 1 and 2 mark the relevant positions on the A ring;the X atom is selected from N (nitrogen) and C (carbon);R is a substituting group on the A ring selected from:

-   -   a group in the 3 (meta) position selected from a linear or        branched C₁-C₅ alkyl, C₂-C₅-alkenyl or C₂-C₅-alkynyl group,        substituted or not-substituted phenyl, linear or branched C₁-C₅        hydroxyalkyl, C₂-C₅-acyl, substituted or not-substituted        benzoyl;    -   a group in the 4 (para) position selected from C₁-C₅ alkyl,        C₂-C₅-alkenyl or C₂-C₅-alkynyl group, C₃-C₆-cycloalkyl,        C₁-C₅-acyloxy, substituted or not-substituted benzoyloxy,        C₁-C₅-acylamino, substituted or not-substituted benzoylamino,        C₁-C₅-sulfonyloxy, substituted or not-substituted        benzenesulfonyloxy, C₁-C₅-alkanesulfonylamino, substituted or        not-substituted benzenesulfonylamino,        C₁-C₅-alkanesulfonylmethyl, substituted or not-substituted        benzenesulfonylmethyl, 2-furyl; 3-tetrahydrofuryl; 2 thiophenyl;        2-tetrahydrothiophenyl groups or a C₁-C₈-alkanoyl, cycloalkanoyl        or arylalkanoyl-C₁-C₅-alkylamino group, such as        acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino group;        Hy is a small hydrophobic group with a steric hindrance factor ν        ranging between 0.5 and 0.9 Å (where ν is the Charton steric        constant for substituents), including methyl, ethyl, chlorine,        bromine, methoxy, trifluoromethyl;        wherein Rd is C₁-C₆-alkyl, C₁-C₆-cycloalkyl, C₁-C₆-alkenyl,

Preferred compounds of formula (Ia) are those wherein, A is benzene,pyridine, pyrimidine, pyrrole, imidazole, furane, thiophene, indole;

Rd is methyl, ethyl or isopropyl;Hy is selected from methyl, ethyl, chlorine, bromine, methoxy,trifluoromethyl.

Particularly preferred compounds of the invention are:

-   (5-acetyl-1-methyl-1H-pyrrol-2-yl)acetyl methanesulphonamide-   (4-isobutyl-2-methylphenyl)acetyl methanesulphonamide-   {2-methyl-4-[(trifluoromethanesulphonyl)amino]phenyl}acetyl    methanesulphonamide-   [1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetylmethanesulphonamide

Compounds of formula (Ia) wherein Rd is above defined are prepared bytransforming a compound of formula (I) wherein YR′ is OH in a reactiveintermediate such as an acylhalide, preferably an acyl chloride, or aknown “active ester”, preferably a benzotriazolyl ester, and reactingwith a compound of formula NH₂SO₂Rd in presence of a suitable base,preferably potassium tert-butoxide. The compounds of the invention,despite of the lack of the methyl group on the propionic chain, arepotent and selective inhibitors of the human PMNs chemotaxis induced byIL-8.

As above discussed, molecules lacking the above methyl group on thechiral carbon atom of the propionic chain have been generally foundinactive in the IL-8 induced chemotaxis assay, owing to the key role ofthe methyl group in mapping the HYDROPHOBIC ALIPHATIC feature of thepharmacophore.

The general superimposition mode of the compounds of the invention tothe pharmacophore hypothesis described above and outlined in FIG. 1, isillustrated in FIGS. 3 and 4.

FIG. 3 illustrates superimposition of the following compounds belongingto the class of arylacetic derivatives:(2-methyl-4-isobutylphenyl)acetic acid;(2-methyl-4-isobutylphenyl)acetyl methanesulphonamide;(2-methyl-4-isobutylphenyl)acetamide.

FIG. 4 illustrates superimposition of the following compounds belongingto the class of arylacetic derivatives:(5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid;(1-benzoyl-2-methyl-1H-indol-3-yl)acetyl methanesulphonamide;(2-chloro-3-benzoylphenyl)acetamide.

The compounds of the invention derive their strong biological activityfrom the unexpected property of the Hydrophobic group (Hy) in the 2position (Formula I) to correctly match the HYDROPHOBIC ALIPHATICfeature of the pharmacophore model represented by the solid spheres inFIGS. 3 and 4. A general pharmacophore superimposition mode is observedindeed for the compounds of formula (I). The Hydrophobic group (Hy) ofthe retrieved ligands which partially or fully map this hypothesisinvariably matches the HYDROPHOBIC ALIPHATIC to feature (solid sphere,FIG. 3). Furthermore, the compounds of formula (I) show the requiredconformational arrangement of the functional groups in order to fully orpartially map the other points of the pharmacophore hypothesis in a lowenergy conformation.

The compounds of the invention have the great advantage of lacking thechiral carbon atom with respect to the known IL-8 inhibitors belongingto the family of 2-arylpropionic acids and derivatives. The process ofmanufacture and purification of the known 2-arylpropionic acids andderivatives requires indeed the development of complicatedenantioselective conditions or the introduction of a step of opticalresolution with the consequential undesired impact on the costs of theactive principle.

The compounds of the invention of formula (I) and (Ia) are generallyisolated in the form of their addition salts with both organic andinorganic pharmaceutically acceptable acids and bases.

Examples of such acids are selected from hydrochloric acid, sulfuricacid, phosphoric acid, metansolfonic acid, fumaric acid, citric acid.

Examples of such bases are selected from sodium hydroxide, potassiumhydroxide, calcium hydroxide, (D,L)-Lysine, L-Lysine, tromethamine.

The compounds of the invention of formula I were evaluated in vitro fortheir ability to inhibit chemotaxis of polymorphonucleate leukocytes(hereinafter referred to as PMNs) and monocytes induced by the fractionsof IL-8 and GRO-α. For this purpose, in order to isolate the PMNs fromheparinized human blood, taken from healthy adult volunteers,mononucleates were removed by means of sedimentation on dextran(according to the procedure disclosed by W. J. Ming et al., J. Immunol.,138, 1469, 1987) and red blood cells by a hypotonic solution. The cellviability was calculated by exclusion with Trypan blue, whilst the ratioof the circulating polymorphonucleates was estimated on thecytocentrifugate after staining with Diff Quick.

Human recombinant IL-8 (Pepro Tech) was used as stimulating agents inthe chemotaxis experiments, giving practically identical results: thelyophilized protein was dissolved in a volume of HBSS containing 0.2%bovin serum albumin (BSA) so thus to obtain a stock solution having aconcentration of 10⁻⁵ M to be diluted in HBSS to a concentration of 10⁻⁹M, for the chemotaxis assays.

During the chemotaxis assay (according to W. Falket et al., J. Immunol.Methods, 33, 239, 1980) PVP-free filters with a porosity of 5 μm andmicrochambers suitable for replication were used.

The compounds of the invention of formula (I) and (Ia) were evaluated ata concentration ranging between 10⁻⁶ and 10⁻¹⁰ M; for this purpose theywere added, at the same concentration, both to the lower pores and theupper pores of the microchamber. Evaluation of the ability of thecompounds of the invention of formula I to inhibit IL-8-inducedchemotaxis of human monocytes was carried out according to the methoddisclosed by Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989).

Particularly preferred is the use of compounds of formula (I) in which Rgroups are 3′-benzoyl, 3′-(4-chloro-benzoyl), 3′-(4-methyl-benzoyl),3′-acetyl, 3′-propionyl, 3′-isobutanoyl,4′-trifluoromethanesulphonyloxy, 4′-benzenesulphonyloxy,4′-trifluoromethanesulphonylamino, 4′-benzenesulphonylamino,4′-benzenesulphonylmethyl, 4′-acetyloxy, 4′-propionyloxy, 4′-benzoyloxy,4′ acetylamino, 4′ propionylamino, 4′-benzoylamino; this activity allowsthe therapeutical use of these compounds in IL-8 related pathologieswhere the CXCR2 pathway is involved specifically or in conjunction withthe CXCR1 signaling.

The dual inhibitors of the IL-8 and GRO-α induced biological activitiesare strongly preferred in view of the therapeutical applications ofinterest, but the described compounds selectively acting on CXCR1 IL-8receptor or CXCR2 GRO-α/IL-8 receptor can find useful therapeuticalapplications in the management of specific pathologies as belowdescribed.

The biological activity of compounds showing high potency either asinhibitors of IL-8 induced PMN chemotaxis (CXCR1) or as dual inhibitorsof IL-8 and GRO-α induced PMN chemotaxis (CXCR1/CXCR2) is reported inTable 1.

TABLE 1 Biological activity data on CXCR1 and CXCR2 receptors (% ofinhibition) IL-8 (c = GRO-α Compound 10⁻⁸ M) (c = 10⁻⁸ M)(5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid 58 ± 11  65 ± 11(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid 60 ± 7  65 ± 5(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetamide 54 ± 10 44 ± 9(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetyl 50 ± 10  46 ± 14methanesulfonamide (4-isobutyl-2-methylphenyl)acetic acid 60 ± 10  4 ± 8(3-isopropyl-2-methylphenyl)acetic acid 62 ± 8   5 ± 10(4-isobutyl-2-methylphenyl)acetyl 67 ± 14  0 ± 10 methanesulfonamide(2-chloro-3-propionylphenyl)acetic acid 67 ± 14 27 ± 8 {2-methyl-4- 60 ±7  52 ± 5 [(trifluoromethanesulphonyl)amino]phenyl}acetylmethanesulphonamide

All the compounds of the invention demonstrated a high degree ofselectivity towards the inhibition of the IL-8 induced chemotaxiscompared to the chemotaxis induced by C5a (10⁻⁹ M) or f-MLP (10⁻⁸ M).

The compounds of formula (I) and (Ia) were found to be totallyineffective as inhibitors of cyclooxygenase (COX) enzymes. In mostcases, the compounds of formula (I) do not interfere with the productionof PGE₂ induced in murine macrophages by lipopolysaccharides stimulation(LPS, 1 μg/mL) at a concentration ranging between 10⁻⁵ and 10⁻⁷ M.Inhibition of the production of PGE₂ which may be recorded, is mostly atthe limit of statistical significance, and more often is below 15-20% ofthe basal value. The reduced effectiveness in the inhibition of the COXconstitutes an advantage for the therapeutical application of compoundsof the invention in as much as the inhibition of prostaglandin synthesisconstitutes a stimulus for the macrophage cells to amplify synthesis ofTNF-α (induced by LPS or hydrogen peroxide) that is an importantmediator of the neutrophilic activation and stimulus for the productionof the cytokine Interleukin-8.

In view of the experimental evidence discussed above and of the roleperformed by Interleukin-8 (IL-8) and congenetics thereof in theprocesses that involve the activation and the infiltration ofneutrophils, the compounds of the invention are particularly useful inthe treatment of a disease such as psoriasis (R. J. Nicholoff et al.,Am. J. Pathol., 138, 129, 1991). Further diseases which can be treatedwith the compounds of the present invention are intestinal chronicinflammatory pathologies such as ulcerative colitis (Y. R. Mahida etal., Clin. Sci., 82, 273, 1992) and melanoma, chronic obstructivepulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis (M.Selz et al., J. Clin. Invest., 87, 463, 1981), idiopathic fibrosis (E.J. Miller, previously cited, and P. C. Cane et al., J. Clin. Invest.,88, 1882, 1991), glomerulonephritis (T. Wada et al., J. Exp. Med., 180,1135, 1994) and in the prevention and treatment of damages caused byischemia and reperfusion.

Inhibitors of CXCR1 and CXCR2 activation find useful applications, asabove detailed, particularly in treatment of chronic inflammatorypathologies (e.g. psoriasis) in which the activation of both IL-8receptors is supposed to play a crucial pathophysiological role in thedevelopment of the disease.

In fact, activation of CXCR1 is known to be essential in IL-8-mediatedPMN chemotaxis (Hammond M et al, J Immunol, 155, 1428, 1995). On theother hand, activation of CXCR2 activation is supposed to be essentialin IL-8-mediated epidermal cell proliferation and angiogenesis ofpsoriatic patients (Kulke R et al., J Invest Dermatol, 110, 90, 1998).

In addition, CXCR2 selective antagonists find particularly usefultherapeutic applications in the management of important pulmonarydiseases like chronic obstructive pulmonary disease COPD (D. W P Hay andH. M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247).

It is therefore a further object of the present invention to provide theuse of compounds of formula (I) and (Ia) in the preparation of amedicament for the treatment of psoriasis, ulcerative colitis, melanoma,chronic obstructive pulmonary disease (COPD), bullous pemphigoid,rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in theprevention and treatment of damages caused by ischemia and reperfusion.The invention also provides compounds of formula (Ia) for use asmedicaments.

Pharmaceutical compositions comprising a compound of the invention and asuitable carrier thereof, are also within the scope of the presentinvention.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may, in fact, be placed into theform of pharmaceutical compositions and unit dosages thereof, and insuch form may be employed as solids, such as tablets or filled capsules,or liquids such as solutions, suspensions, emulsions, elixirs, orcapsules filled with the same, all for oral use, or in the form ofsterile injectable solutions for parenteral (including subcutaneous)use. Such pharmaceutical compositions and unit dosage forms thereof maycomprise ingredients in conventional proportions, with or withoutadditional active compounds or principles, and such unit dosage formsmay contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

When employed as pharmaceuticals, the arylacetic acids of this inventionand their derivatives are typically administered in the form of apharmaceutical composition. Such compositions can be prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. Generally, the compounds of this invention areadministered in a pharmaceutically effective amount. The amount of thecompound actually administered will typically be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of the invention can be administered bya variety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Depending on the intendedroute of delivery, the compounds are preferably formulated as eitherinjectable or oral compositions. The compositions for oraladministration can take the form of bulk liquid solutions orsuspensions, or bulk powders. More commonly, however, the compositionsare presented in unit dosage forms to facilitate accurate dosing. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient. Typical unit dosage forms include prefilled,premeasured ampoules or syringes of the liquid compositions or pills,tablets, capsules or the like in the case of solid compositions. In suchcompositions, the acetic acid compound or its derivative usually a minorcomponent (from about 0.1 to about 50% by weight or preferably fromabout 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Liquid forms, including theinjectable compositions described herebelow, are always stored in theabsence of light, so as to avoid any catalytic effect of light, such ashydroperoxide or peroxide formation. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the arylacetic acid derivative offormula I in such compositions is typically a minor component,frequently ranging between 0.05 to 10% by weight with the remainderbeing the injectable carrier and the like. The mean daily dosage willdepend upon various factors, such as the seriousness of the disease andthe conditions of the patient (age, sex and weight). The dose willgenerally vary from 1 mg or a few mg up to 1500 mg of the compounds offormula (I) per day, optionally divided into multiple administrations.Higher dosages may be administered also thanks to the low toxicity ofthe compounds of the invention over long periods of time.

The above described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 8 of “Remington'sPharmaceutical Sciences Handbook”, 18^(th) Edition, 1990, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in the Remington's Handbook asabove.

The present invention shall be illustrated by means of the followingexamples which are not construed to be viewed as limiting the scope ofthe invention.

Materials and Methods

Synthesis of Arylacetic Acids

Example 1 3-benzoyl-2-methylphenyl)acetic acid

Starting from the commercial reagent 2-hydroxy benzophenone andfollowing the experimental procedure described in Italian Patent1,283,649, 1-[(2′-hydroxy-3′-benzoyl)phenyl]prop-2-ene has beensynthesised in good yield (>75%).

To a cooled (T=−15° C.) solution of1-[(2′-hydroxy-3′-benzoyl)phenyl]prop-2-ene (33 mmol) in dry CH₂Cl₂ (70ml) N,N-diisopropylethylamine (59.7 mmol) is added and the resultingsolution is left stirring for 30′ at T=−15° C. Thentrifluoromethanesulfonic anhydride (40.16 mmol) is dropped into thesolution and at the end of the adding the mixture is left stirring for 1h. The mixture is quenched with 2N HCl (100 mL) and the two phases areseparated and debated; the organic one is washed again with 2N HCl (100mL), with water (2×100 mL) and with a saturated solution of NaCl (2×70ml), dried on Na₂SO₄ and evaporated under reduced pressure to give1-[(2-trifluoromethanesulfonyloxy-3-benzoyl)phenyl]prop-2-ene (31.3mmol) as an oily crude pure enough to be used in the following step.

To a solution of1-[(2-trifluoromethanesulfonyloxy-3-benzoyl)phenyl]prop-2-ene (30 mmol)in CH₂Cl₂ (90 ml) water (90 mL), acetic acid (18.2 mL) and Aliquat (1.46mmol) are added. KMnO₄ (103 mmol) is added portionwise in 90′. At theend of the addings the mixture is left under stirring overnight. A 10%solution of sodium metabisulfite is added dropwise until completebleaching of the solution. The two phases are debated and separated andthe organic one is washed back with a saturated solution of NaCl (2×50ml), dried on Na₂SO₄ and evaporated under reduced pressure to give anoily crude that, after flash cromatography, gives1-[(2-trifluoromethanesulfonyloxy-3-benzoyl)phenyl]acetic acid (15 mmol)as pale yellow oil.

¹H-NMR (CDCl₃): δ 7.85 (m, 2H); 7.68 (m, 2H); 7.45 (m, 4H); 3.90 (s,2H); 2.20 (bs, 1H, COOH).

1-[(2-trifluoromethanesulfonyloxy-3-benzoyl)phenyl]acetic acid (10.3mmol) is dissolved in methyl alcohol (30 mL) and 96% H₂SO₄ (0.2 mL) isadded. After stirring overnight at room temperature, the solvent isevaporated under reduced pressure and the crude is diluted with CH₂Cl₂(50 ml) and washed with water (3×50 mL), dried on Na₂SO₄ and evaporatedunder reduced pressure to give1-[(2-trifluoromethanesulfonyloxy-3-benzoyl)phenyl]acetic acid methylester as yellow oil (9.2 mmol).

¹H-NMR (CDCl₃): δ 7.80 (m, 2H); 7.65 (m, 2H); 7.45 (m, 4H); 3.90 (s,2H); 3.72 (s, 3H).

Starting from 1-[(2-trifluoromethanesulfonyloxy-3-benzoyl)phenyl]aceticacid methyl ester, 2-methyl derivative has been prepared by means ofreacting said triflate with organostannanes according the methodsdescribed by Mitchell T. N., Synthesis, 803, 1992 and Ritter K.,Synthesis, 735, 1993.

The acid has been synthesized starting from1-[(2-trifluoromethanesulfonyloxy-3-benzoyl)phenyl]acetic acid methylester (7.5 mmol) which has been dissolved in dry N-methyl-2-pirrolidone(25 ml); to the mixture anhydrous LiCl (22.5 mmol), triphenylarsine (0.3mmol) and dipalladiumtribenzylidenacetone (0.14 mmol Pd) have beenadded. After 5′ at r.t. tetramethyltin (8.4 mmol) is added and thesolution is stirred for 3 h at T=60° C. After cooling the solution tor.t., the mixture is diluted with n-hexane and a saturated solution ofKF is added; after filtration and separation of the phases, the organicphase is dried over Na₂SO₄ and evaporated under vacuum. The purificationof the residue by means of flash chromatography gives(3-benzoyl-2-methylphenyl)acetic acid methyl ester. (Ritter K.,Synthesis, 735, 1993 and Mitchell T. N., Synthesis, 803, 1992).

1N NaOH (5 ml) was added to a solution of the ester in 1,4-dioxane (5ml) and the solution is stirred at room temperature overnight. Aftersolvent evaporation the mixture is acidified to pH=2 with 2N HCl untilcomplete precipitation of the product, which is isolated as a whitesolid by filtration.

¹H-NMR (CDCl₃): δ 10.50 (bs, 1H, COOH); 7.80 (m, 2H); 7.65 (m, 2H); 7.45(m, 4H); 3.45 (s, 2H); 2.25 (s, 3H).

Example 2 (3-isopropyl-2-methylphenyl)acetic acid

According to the procedure described in Italian Patent 1,283,649 andstarting from the commercial reagent T-hydroxyacetophenone, theintermediate 1-[(2-trifluoromethanesulfonyloxy-3-isopropyl)phenyl]aceticacid methyl ester has been synthesised.

¹H-NMR (CDCl₃): δ 7.55-7.40 (m, 3H); 3.85 (s, 2H); 3.70 (s, 3H); 2.45(s, 3H).

A solution of1-[(2-trifluoromethanesulfonyloxy-3-isopropyl)phenyl]acetic acid methylester (7.5 mmol) in dry THF (Tetrahydrofuran) (5 mL) is slowly droppedinto a mixture of methyltriphenylphosphonium bromide (7.5 mmol) andn-BuLi (7.5 mmol; 1.6 M in n-hexane) in thy THF (10 mL). At the end ofthe addings the mixture is left under stirring overnight at roomtemperature. A 10% solution of sodium metabisulfite (20 mL) is addeddropwise and the two phases are debated and separated; the organic phaseis dried over Na₂SO₄ and evaporated under vacuum. The purification ofthe residue by means of flash chromatography gives1-[(2-trifluoromethanesulfonyloxy-3-isopropen-2′-yl)phenyl]acetic acidmethyl ester as colourless oil (5.28 mmol).

¹H-NMR (CDCl₃): δ 7.55-7.40 (m, 3H); 5.50 (s, 2H); 3.80 (s, 2H); 3.74(s, 3H); 1.63 (s, 3H).

The reduction of1-[(2-trifluoromethanesulfonyloxy-3-isopropen-2′-yl)phenyl]acetic acidmethyl ester has been carried out by hydrogenolysis with Pd/C inabsolute ethyl alcohol to give after catalyst filtration and motherliquors evaporation under reduced pressure, pure(3-isopropyl-2-methylphenyl)acetic acid methyl ester as pale yellow oil(5 mmol).

¹H-NMR (CDCl₃): δ 7.52-7.45 (m, 3H); 3.82 (s, 2H); 3.70 (s, 3H); 2.65(m, 1H); 1.25 (d, 6H, J=8 Hz).

Following the procedure described for Example 1 and starting from(3-isopropyl-2-methylphenyl)acetic acid methyl ester (7.0 mmol) pure(3-isopropyl-2-methylphenyl)acetic acid has been synthesised (5.45mmol).

¹H-NMR (CDCl₃): δ 11.2 (bs, 1H, COOH); 7.35-7.20 (m, 3H); 3.80 (s, 2H);2.55 (m, 1H); 2.22 (s, 3H); 1.28 (d, 6H, J=8 Hz).

Example 3 (2-chloro-3-propionylphenyl)acetic acid

According to the procedure described in Italian Patent 1,283,649 andstarting from the commercial reagent 2′-hydroxypropiophenone, theintermediate 1-[(2-hydroxy-3-propionyl)phenyl]prop-2-ene has beensynthesised.

By treatment of the compound by PhPCl₄, according to the proceduredescribed by Bay et al., J. Org. Chem., Vol. 32, 3415, 1990,1-[(2-chloro-3-propionyl)phenyl]prop-2-ene (5.1 mmol). Following theprocedure for the double bond oxidation described in the Example 1, pure(2-chloro-3-propionylphenyl)acetic acid has been synthesised (4.15mmol).

¹H-NMR (CDCl₃): δ 10.18 (bs, 1H, COOH); 7.40-7.24 (m, 3H); 3.65 (s, 2H);2.75 (q, 2H, J₁=8 Hz, J₂=3 Hz); 1.15 (t, 3H, J=8 Hz).

Example 4 (4-isobutyl-2-methylphenyl)acetic acid

The compound has been prepared by double Stille reaction on the startingreagent 2-(2-acetoxy-4-perfluorbutanesulfonyloxy)phenylacetic acidmethyl ester (prepared according known procedures) following the sameexperimental procedure used for the synthesis of analogous arylpropionicacids and described in WO 01/58852 A2.

¹H-NMR (CDCl₃): δ 7.22 (d, 1H, J=8 Hz); 7.05 (d, 1H, J=8 Hz); 6.92 (s,1H); 3.50 (s, 2H); 2.40 (d, 2H, J=7 Hz); 2.20 (s, 3H); 1.95 (m, 1H);0.95 (d, 6H, J=7 Hz).

Example 5 {2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid

The synthesis of the compound has been carried out as follows:

the commercial reagent 2-hydroxy-4-nitrobenzoic acid has beentransformed into 2-hydroxy-4-nitroacetophenone by the Meldrum's acidpathway to methyl ketones, according to the experimental proceduredescribed by Hase T. A. et al., Synthetic Communications, 10(3),221-224, 1980. The treatment of 2-hydroxy-4-nitroacetophenone withtrifluoromethanesulfonic anhydride has given the2-trifluoromethanesulfonyloxy derivative that, by Stile reactionaccording the experimental procedure described in Example 1, hasafforded the 2-methyl-4-nitroacetophenone.

Starting from 2-methyl-4-nitroacetophenone and following the proceduredescribed in Italian Patent 1,283,649 the 2-methyl-4-nitro phenylaceticacid methyl ester has been synthesised.

¹H-NMR (CDCl₃): δ 7.50-7.42 (m, 3H); 3.80 (s, 2H); 3.64 (s, 3H); 2.25(s, 3H).

To a solution of 2-methyl-4-nitro phenylacetic acid methyl ester (10mmol) in dry THF (20 mL) and methyl alcohol (20 mL), ammonium formate(0.1 mol) and 10% Pd/C (0.5 g) have been added and the resulting mixturehas been left stirring for 3 h, until complete disappearance of thestarting reagent. The catalyst has been filtered off and the filtrateevaporated under vacuum to give 2-methyl-4-amino phenylacetic acidmethyl ester as a waxy solid (9.22 mmol).

¹H-NMR (CDCl₃): δ 7.51 (m, 1H); 7.40 (m, 1H); 7.15 (m, 1H); 5.00 (bs,2H, NH ₂); 3.82 (s, 2H); 3.65 (s, 3H); 2.20 (s, 3H).

To a solution of 2-methyl-4-amino phenylacetic acid methyl ester (5.3mmol) in acetone (10 mL) dry pyridine (7.95 mmol) and phenylsulfonylchloride (6.36 mmol) have been added and the resulting solution has beenleft stirring overnight at room temperature. Acetone has been evaporatedand the residue diluted with CHCl₃ (15 mL), washed with 1N HCl (2×10mL), water (3×20 mL), dried over Na₂SO₄ and evaporated under vacuum togive {2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid methyl esteras colourless oil (5.0 mmol) pure to be used in the following reaction.Following the procedure described for Example 1 and starting from themethyl ester (5.0 mmol) pure{2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid has beensynthesised (4.75 mmol).

¹H-NMR (CDCl₃): δ 9.40 (s, 1H, SO₂NH); 7.73 (m, 2H); 7.42 (m, 3H); 7.50(m, 1H); 7.45 (m, 1H); 7.15 (m, 1H); 3.82 (s, 2H); 2.21 (s, 3H).

According to the same experimental procedure and using as reagenttrifluoromethanesulfonic anhydride, the following compound has beensynthesised:

Example 6 {2-methyl-4-[(trifluoromethanesulfonyl)amino]phenyl}aceticacid

¹H-NMR (CDCl₃): δ 9.35 (s, 1H, SO₂NH); 7.54 (m, 1H); 7.40 (m, 1H); 7.20(m, 1H); 3.80 (s, 2H); 2.25 (s, 3H).

Example 7 {2-chloro-4-[(trifluoromethanesulfonyl)oxy]phenyl}acetic acid

Starting from the intermediate 2-hydroxy-4-nitroacetophenone (describedin the Example 5), the synthesis of the 2-chloro derivative has beencarried out following the experimental procedure described by Bay etal., J. Org. Chem., Vol. 32, 3415, 1990. The intermediate2-chloro-4-nitroacetophenone has been transformed into the intermediate2-chloro-4-amino phenylacetic acid methyl ester according the sameprocedure described in Example 5.

¹H-NMR (CDCl₃): δ 7.55-7.45 (m, 3H); 3.85 (s, 2H); 3.60 (s, 3H).

After treatment of 2-chloro-4-amino phenylacetic acid methyl ester withsodium nitrite in acidic conditions and following replacement of thediazonium ion with the hydroxyl group as described in Organic Synthesis,III, 453, (2-chloro-4-hydroxyphenyl)acetic acid has been obtained aswhite solid.

¹H-NMR (CDCl₃): δ 7.74-7.60 (m, 3H); 6.35 (bs, 1H, OH); 3.85 (s, 2H).

A mixture of the above described (2-chloro-4-hydroxyphenyl)acetic acid(2 mmol), trifluoromethanesulfonic anhydride (4 mmol) in dry pyridine (1mL) has been warmed at T=60° C. for 24 hours. After cooling at roomtemperature the reaction mixture has been poured into 1 N HCl (5 mL) andthe aqueous solution extracted with CH₂Cl₂ (3×10 mL). The collectedorganic extracts have been washed back with 1N NaOH (2×10 mL), driedover Na₂SO₄ and evaporated under reduced pressure to give a cruderesidue. The crystallisation in isopropyl ether of the crude has giventhe pure {2-chloro-4-[(trifluoromethanesulfonyl)oxy]phenyl}acetic acidas white solid (1.25 mmol).

¹H-NMR (CDCl₃): δ 7.70-7.62 (m, 3H); 3.85 (s, 2H).

Example 8 (5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid

The compound has been synthesised starting from the commercial reagents1-methyl-2-pyrrolecarboxaldehyde and benzoyl chloride and following theexperimental procedure described in Di Santo R. et al. Synth. Comm.,25(6), 787-793 (1995).

¹H-NMR (CDCl₃): δ 7.85 (m, 2H); 7.52 (m, 1H); 7.45 (m, 2H); 6.70 (s,1H); 6.15 (s, 1H); 3.97 (s, 3H); 3.75 (s, 2H); 3.0 (bs, 1H, COOH).

According the same experimental procedures and starting from the relatedcommercial acyl chlorides, the following compounds have been prepared:

Example 9 [1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]acetic acid

¹H-NMR (CDCl₃): δ 7.82 (d, 2H, J=8 Hz); 7.58 (d, 2H, J=8 Hz); 7.20 (s,1H); 6.68 (s, 1H); 3.75 (s, 2H); 3.70 (s, 3H).

Example 10 [1-methyl-5-[(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid

¹H-NMR (CDCl₃): δ 7.80 (d, 2H, J=8 Hz); 7.55 (d, 2H, J=8 Hz); 7.18 (s,1H); 6.72 (s, 1H); 3.75 (s, 2H); 3.70 (s, 3H); 2.35 (s, 3H).

Example 11 (5-acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid

¹H-NMR (CDCl₃): δ 6.90 (d, 1H, J=3 Hz); 6.05 (d, 1H, J=3 Hz); 3.80 (s,3H); 3.62 (s, 2H); 2.32 (s, 3H).

Example 12 (5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid

¹H-NMR (CDCl₃): δ 7.55 (s, 1H); 6.32 (s, 1H); 3.65 (s, 2H); 3.52 (s,3H); 3.15 (m, 1H); 1.05 (d, 6H, J=7 Hz).

Example 13 (1-benzoyl-2-methyl-1H-pyrrol-3-yl)acetic acid

The intermediate (2-methyl-1H-pyrrol-3-yl)acetic acid ethyl ester hasbeen synthesised as described in Bertschy H., et al., Angew. Chem. Int.Ed. Engl. 29(7), 777-778 (1990).

The following N-benzoylation and ester hydrolysis according well knownprocedures (NaH/benzoyl chloride) give the desired product.

¹H-NMR (CDCl₃): δ 8.15 (m, 2H); 7.60 (m, 1H); 7.45 (m, 2H); 6.95 (d, 1H,J=3 Hz); 6.32 (d, 1H, J=3 Hz); 4.50 (bs, 1H, COOH); 3.85 (s, 2H); 2.35(s, 3H).

Example 14 (1-benzoyl-2-chloro-1H-pyrrol-3-yl)acetic acid

The product has been synthesised by a multistep synthesis according wellknown literature procedures. The condensation of the commercial reagentdiethyl malonate with bromoacetaldehyde dimethyl acetal and the acetalhydrolysis allows to obtain the intermediate aldehyde which, aftertreatment with gaseous ammonia and dehydration of the not isolatedintermediate enamine, gives the pure intermediate2-hydroxypyrrole-3-acetic acid ethyl ester.

¹H-NMR (CDCl₃): δ 10.35 (bs, 1H, NH); 7.21 (d, 1H, J=3 Hz); 7.05 (bs,1H, OH); 6.35 (d, 1H, J=3 Hz); 4.12 (q, 2H, J=7 Hz); 3.45 (s, 2H); 1.31(t, 3H, J=7 Hz).

The pyrrole intermediate, after treatment with PCl₅, gives the 2-chloroderivative which, after ester hydrolysis in usual conditions(NaOH/CH₃OH) and N-benzoylation, affords the pure compound(1-benzoyl-2-chloro-1H-pyrrol-3-yl)acetic acid as white solid (yield78%).

¹H-NMR (DMSO-d₆); δ 8.15 (m, 2H); 7.60 (m, 1H); 7.45 (m, 2H); 6.92 (d,1H, J=3 Hz); 6.35 (d, 1H, J=3 Hz); 4.65 (bs, 1H, COOH); 3.82 (s, 2H).

Example 15 (1-benzoyl-2-methyl-1H-indol-3-yl)acetic acid

The commercial reagent 2-methyl-3-indoleacetic acid (3 mmol) has beentreated with NaH (6.6 mmol) and benzoyl chloride (6.6 mmol) in dry THF(10 mL) according well known procedures. The usual reaction work up andcrystallisation of the residue in isopropyl ether led to the pure(1-benzoyl-2-methyl-1H-indole-3-yl)acetic acid as white solid (2.25mmol).

¹H-NMR (CDCl₃): δ 7.82-7.70 (m, 3H); 7.55 (t, 2H, J=8.5 Hz); 6.90-6.80(m, 2H); 6.65 (m, 2H); 3.62 (s, 2H); 3.30 (s, 3H).

Example 16 [1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetic acid

The commercial reagent 2-methyl-3-indoleacetic acid (3 mmol) has beentreated with NaH (6.6 mmol) and 4-chlorobenzoyl chloride (6.6 mmol) indry THF (10 mL) according well known procedures. The usual reaction workup and crystallisation of the residue in isopropyl ether led to the pure[1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetic acid as white solid(2.01 mmol).

¹H-NMR (CDCl₃): δ 7.80-7.70 (t, 2H, J=8.5 Hz); 7.55 (t, 2H, J=8.5 Hz);6.90 (s, 1H); 6.80 (m, 1H); 3.60 (s, 2H); 3.30 (s, 3H).

Example 17 (1-isopropyl-2-methyl-1H-pyrrole[2,3-b]pyridin-3-yl)aceticacid

The commercial reagent 1H-pyrrole[2,3-b]pyridine (3 mmol) has beentreated with NaH (3.3 mmol) and isopropyl chloride (3.3 mmol) in dry THF(10 mL) according well known procedures. The usual reaction work up andpurification of the residue by chromatography led to the pure1-isopropyl-1H-pyrrole[2,3-b]pyridine as white solid (2.83 mmol).

¹H-NMR (CDCl₃): δ 7.65 (m, 1H); 7.15-7.08 (m, 2H); 7.00 (m, 1H); 6.50(m, 1H); 3.12 (m, 1H); 1.05 (d, 6H, J=7 Hz).

Following the experimental procedure described by Chi S. M. et al.,Tetrahedron Letters, 41, 919-922 (2000) and starting from1-isopropyl-1H-pyrrole[2,3-b]pyridine (2.5 mmol),(1-isopropyl-2-methyl-1H-pyrrole[2,3-b]pyridin-3-yl)ethoxy acetate hasbeen isolated (2.0 mmol). The final oxidation by KMnO₄ in phase transfercatalysis conditions (described in Example 1) has led to the desiredproduct (1-isopropyl-2-methyl-1H-pyrrole[2,3-b]pyridin-3-yl)acetic acid(1.85 mmol).

¹H-NMR (CDCl₃): δ 7.15 (m, 1H); 7.10 (m, 1H); 6.95 (m, 1H); 3.55 (s,2H); 3.11 (m, 1H); 2.35 (s, 3H); 1.05 (d, 6H, J=7 Hz).

Example 18 (3-benzoyl-2-methoxyphenyl)acetic acid

(3-benzoyl-2-hydroxyphenyl)acetic acid methyl ester, prepared accordingknow procedures from 2-hydroxybenzophenone, has been treated withpotassium carbonate and iodomethane in acetone to give the corresponding2-methoxy derivative that, after usual hydrolysis (NaOH/CH₃OH) has given(3-benzoyl-2-methoxyphenyl)acetic acid as white solid.

¹H-NMR (CDCl₃): δ 7.90 (d, 2H, J=7 Hz); 7.62 (m, 1H); 7.50-7.40 (m, 3H);7.35 (m, 1H); 7.15 (t, 1H, J=7 Hz); 3.82 (s, 2H); 3.60 (s, 3H).

Synthesis of Arylacetic Amides

According to the experimental procedure described in WO 01/58852 andstarting from the related acetic acid, the following compounds have beensynthesised:

Example 19 (5-acetyl-1-methyl-1H-pyrrol-2-yl)acetamide

¹H-NMR (CDCl₃): δ 6.92 (d, 1H, J=3 Hz); 6.05 (d, 1H, J=3 Hz); 5.25 (bs,2H, CONH ₂); 3.81 (s, 3H); 3.68 (s, 2H); 2.35 (s, 3H).

Example 20 (5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-carboxymethylacetamide

¹H-NMR (CDCl₃): δ 6.90 (d, 1H, J=3 Hz); 6.05 (d, 1H, J=3 Hz); 5.95 (d,1H, J=7 Hz, CONH); 4.05 (d, 2H, J=7 Hz); 3.81 (s, 3H); 3.68 (s, 2H);2.35 (s, 3H).

Example 21(S)(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxyethyl)acetamide

¹H-NMR (CDCl₃): δ 6.92 (d, 1H, J=3 Hz); 6.05 (d, 1H, J=3 Hz); 6.00 (bs,1H, CONH); 4.53 (q, 1H, J=7 Hz); 3.81 (s, 3H); 3.68 (s, 2H); 2.35 (s,3H); 1.55 (d, 3H, J=7 Hz).

Example 22(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(3-dimethylaminopropyl)acetamide

¹H-NMR (CDCl₃): δ 7.75 (bs, 1H, CONH); 6.92 (d, 1H, J=3 Hz); 6.28 (d,1H, J=3 Hz); 4.10 (s, 3H); 3.80 (s, 2H); 3.54 (m, 2H); 2.48 (t, 2H, J=7Hz); 2.40 (s, 3H); 2.19 (s, 6H); 1.76 (m, 2H).

Example 23(S)(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(1-carboxy-2-methoxyethyl)acetamide

¹H-NMR (CDCl₃): δ 7.45 (bs, 1H, CONH); 6.92 (d, 1H, J=3 Hz); 6.05 (d,1H, J=3 Hz); 4.53 (q, 1H, J=7 Hz); 3.81 (s, 3H); 3.68 (s, 2H); 3.20 (s,3H); 3.15 (d, 2H, J=7 Hz); 2.35 (s, 3H).

Example 24 (4-isobutyl-2-methylphenyl)acetamide

¹H-NMR (CDCl₃): δ 7.20 (d, 1H, J=8 Hz); 7.05 (d, 1H, J=8 Hz); 6.95 (s,1H); 5.70 (bs, 2H, CONH ₂); 3.68 (s, 2H); 2.40 (d, 2H, J=7 Hz); 2.22 (s,3H); 1.95 (m, 1H); 0.95 (d, 6H, J=7 Hz).

Example 25(2-chloro-3-propionylphenyl)-N-(3-dimethylaminoethyl)acetamide

¹H-NMR (CDCl₃): δ 7.50 (bs, 1H, CONH); 7.40-7.24 (m, 3H); 3.62 (s, 2H);3.54 (m, 2H); 2.75 (q, 2H, J₁=8 Hz, J₂=3 Hz); 2.25 (t, 2H, J=7 Hz); 2.19(s, 6H); 1.15 (t, 3H, J=8 Hz).

Example 26(3-isopropyl-2-methylphenyl)-N-[3-(1-piperidinyl)propyl]acetamide

¹H-NMR (CDCl₃): δ 7.45 (bs, 1H, CONH); 7.35-7.20 (m, 3H); 3.80 (s, 2H);3.50 (m, 2H); 3.32 (m, 2H); 2.95 (m, 2H); 2.55 (m, 1H); 2.45 (m, 2H);2.22 (s, 3H); 2.10 (m, 2H); 1.90 (m, 6H); 1.28 (d, 6H, J=8 Hz).

Example 27 (3-benzoyl-2-methylphenyl)acetamide

¹H-NMR (CDCl₃): δ 7.82 (m, 2H); 7.60 (m, 2H); 7.45 (m, 4H); 5.45 (bs,2H, CONH ₂); 3.70 (s, 2H); 2.25 (s, 3H).

Example 28 (1-benzoyl-2-methyl-1H-indol-3-yl)acetamide

¹H-NMR (CDCl₃): δ 7.82-7.70 (m, 3H); 7.55 (t, 2H, J=8.5 Hz); 6.90-6.80(m, 2H); 6.65 (m, 2H); 5.75 (bs, 2H, CONH ₂); 3.68 (s, 2H); 3.30 (s,3H).

Example 29(1-benzoyl-2-methyl-1H-indol-3-yl)-N-(3-dimethylaminopropyl)acetamide

¹H-NMR (CDCl₃): δ 7.80-7.72 (m, 3H); 7.60 (bs, 1H, CONH); 7.55 (t, 2H,J=8.5 Hz); 6.90-6.80 (d, 2H, J=8 Hz); 6.65 (d, 2H, J=8 Hz); 3.80 (s,2H); 3.58 (m, 2H); 3.30 (s, 3H); 2.50 (t, 2H, J=7 Hz); 2.20 (s, 6H);1.80 (m, 2H).

Example 30 [1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetamide

¹H-NMR (CDCl₃): δ 7.80-7.70 (m, 2H, J=8.5 Hz); 7.55 (t, 2H, J=8.5 Hz);6.92-6.80 (d, 2H, J=8 Hz); 6.68 (d, 2H, J=8 Hz); 5.62 (bs, 2H, CONH ₂);3.70 (s, 2H); 3.30 (s, 3H).

Example 31[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide

¹H-NMR (CDCl₃): δ 7.82-7.75 (m, 2H, J=8.5 Hz); 7.55 (m, 2H); 6.92-6.70(m, 3H); 5.60 (bs, 2H, CONH ₂); 3.82 (s, 3H); 3.66 (s, 2H); 3.30 (s,3H).

Example 32{2-chloro-4-[(trifluoromethanesulfonyl)oxy]phenyl}-N-(2-hydroxyethoxyethyl)acetamide

¹H-NMR (CDCl₃): δ 7.70-7.62 (m, 3H); 5.90 (bs, 1H, CONH); 3.80 (s, 2H);3.65 (m, 2H); 3.55-3.32 (m, 6H); 2.05 (bs, 1H, OH).

Example 33(1-benzoyl-2-methyl-1H-pyrrol-3-yl)-N-(2-methoxyethyl)acetamide

¹H-NMR (CDCl₃): δ 8.12 (m, 2H); 7.60 (m, 1H); 7.50 (m, 2H); 6.92 (d, 1H,J=3 Hz); 6.32 (d, 1H, J=3 Hz); 5.65 (bs, 1H, CONH); 3.75 (s, 2H); 3.25(t, 2H, J=8 Hz); 3.20 (s, 3H); 2.97 (m, 2H); 2.35 (s, 3H).

Example 34(1-benzoyl-2-chloro-1H-pyrrol-3-yl)-N-[3-(1-morpholino)propyl]acetamide

¹H-NMR (CDCl₃): δ 8.15 (m, 2H); 7.60 (m, 1H); 7.45 (m, 2H); 6.92 (d, 1H,J=3 Hz); 6.35 (d, 1H, J=3 Hz); 6.20 (bs, 1H, CONH); 3.78 (s, 2H); 3.25(m, 4H); 2.98 (m, 2H); 2.45 (m, 6H); 1.80 (m, 2H).

Example 35 (5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetamide

¹H-NMR (CDCl₃): δ 7.50 (s, 1H); 6.35 (s, 1H); 5.85 (bs, 2H, CONH ₂);3.77 (s, 2H); 3.50 (s, 3H); 3.18 (m, 1H); 1.05 (d, 6H, J=7 Hz).

Example 36(5-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxymethyl)acetamide

¹H-NMR (CDCl₃): δ 10.53 (bs, 1H, COOH), 7.85 (m, 2H); 7.52 (m, 1H); 7.45(m, 2H); 6.70 (s, 1H); 6.15 (s, 1H); 5.95 (d, 1H, J=7 Hz, CONH); 4.05(d, 2H, J=7 Hz) 3.95 (s, 3H); 3.68 (s, 2H).

Example 37[1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]-N-(2-hydroxyethoxyethyl)acetamide

¹H-NMR (CDCl₃): δ 7.82 (d, 2H, J=8 Hz); 7.55 (d, 2H, J=8 Hz); 7.40 (bs,1H, CONH); 7.35 (s, 1H); 6.65 (s, 1H); 3.70 (s, 2H); 3.65 (s, 3H); 3.60(m, 2H); 3.50-3.42 (m, 6H); 2.25 (bs, 1H, OH).

Example 38 [1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]acetamide

¹H-NMR (CDCl₃): δ 7.82 (d, 2H, J=8 Hz); 7.58 (d, 2H, J=8 Hz); 7.20 (s,1H); 6.68 (s, 1H); 6.35 (bs, 2H, CONH ₂); 3.70 (s, 3H); 3.66 (s, 2H).

Example 39{2-methyl-4-[(phenylsulphonyl)amino]phenyl}-N-(3-dimethylaminopropyl)acetamide

¹H-NMR (CDCl₃); δ 9.20 (s, 1H, SO₂NH); 7.75 (m, 2H); 7.65 (bs, 1H,CONH); 7.42 (m, 3H); 7.50 (m, 1H); 7.45 (m, 1H); 7.12 (m, 1H); 3.88 (s,2H); 3.58 (m, 2H); 2.50 (t, 2H, J=7 Hz); 2.35 (s, 6H); 2.21 (s, 3H);1.80 (m, 2H).

Example 40 (3-benzoyl-2-methoxyphenyl)acetamide

¹H-NMR (CDCl₃): δ 7.90 (d, 2H, J=7 Hz); 7.62 (m, 1H); 7.50-7.40 (m, 3H);7.35 (m, 1H); 7.15 (t, 1H, J=7 Hz); 6.55 (bs, 2H, CONH ₂); 3.82 (s, 3H);3.66 (s, 2H).

Synthesis of Arylacetic Methanesulfonamides

According to the experimental procedure described in WO 00/24710 andstarting from the related acetic acid, the following compounds have beensynthesised:

Example 41 (5-acetyl-1-methyl-1H-pyrrol-2-yl)acetyl methanesulfonamide

¹H-NMR (CDCl₃): δ 7.50 (bs, 1H, CONH); 6.90 (d, 1H, J=3 Hz); 6.05 (d,1H, J=3 Hz); 3.80 (s, 3H); 3.58 (s, 2H); 3.22 (s, 3H); 2.32 (s, 3H).

Example 42 (4-isobutyl-2-methylphenyl)acetyl methanesulfonamide

¹H-NMR (CDCl₃): δ 7.20 (d, 1H, J=8 Hz); 7.10 (bs, 1H, CONH); 7.00 (d,1H, J=8 Hz); 6.85 (s, 1H); 3.65 (s, 2H); 3.22 (s, 3H); 2.40 (d, 2H, J=7Hz); 2.22 (s, 3H); 1.95 (m, 1H); 0.95 (d, 6H, J=7 Hz).

Example 43 {2-methyl-4-[(trifluoromethanesulfonyl)amino]phenyl}acetylmethanesulfonamide

¹H-NMR (CDCl₃): δ 9.42 (bs, 1H, SO₂NH); 7.45 (bs, 1H, CONH); 7.52 (m,1H); 7.45 (m, 1H); 7.20 (m, 1H); 3.85 (s, 2H); 3.45 (s, 3H); 2.25 (s,3H).

Example 44 [1-methyl-5-[(4-methylbenzoyl)-1H-pyrrol-2-yl]acetylmethanesulfonamide

¹H-NMR (CDCl₃); δ 7.80 (d, 2H, J=8 Hz); 7.55 (d, 2H, J=8 Hz); 7.38 (bs,1H, CONH); 7.18 (s, 1H); 6.72 (s, 1H); 3.82 (s, 2H); 3.70 (s, 3H); 3.42(s, 3H); 2.35 (s, 3H).

Table II reports chemical name and structure formula for the compoundsof Examples 1-44.

TABLE (II) N. Compound name Structure formula 1(3-benzoyl-2-methylphenyl)acetic acid

2 (3-isopropyl-2-methylphenyl)acetic acid

3 (2-chloro-3-propionylphenyl)acetic acid

4 (4-isobutyl-2-methylphenyl)acetic acid

5 {2-methyl-4-[(phenylsulfonyl)amino] phenyl}acetic acid

6 (2-methyl-4-([(trifluoromethyl)sulfonyl] amino}phenyl)acetic acid

7 (2-chloro-4-{[(trifluoromethyl)sulfonyl] oxy}phenyl)acetic acid

8 (5-benzoyl-1-methyl-1H- pyrrol-2-yl)acetic acid

9 [5-(4-chlorobenzoyl)-1-methyl- 1H-pyrrol-2-yl]acetic acid

10 [1-methyl-5-(4-methylbenzoyl)- 1H-pyrrol-2-yl]acetic acid

11 (5-acetyl-1-methyl-1H- pyrrol-2-yl)acetic acid

12 (5-isobutyryl-1-methyl-1H- pyrrol-2-yl)acetic acid

13 (1-benzoyl-2-methyl-1H- pyrrol-3-yl)acetic acid

14 (1-benzoyl-2-chloro-1H- pyrrol-3-yl)acetic acid

15 (1-benzoyl-2-methyl-1H- indol-3-yl)acetic acid

16 [1-(4-chlorobenzoyl)-2-methyl- 1H-indol-3-yl]acetic acid

17 (1-isopropyl-2-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl)acetic acid

18 (3-benzoyl-2-methoxyphenyl)acetic acid

19 (5-acetyl-1-methyl-1H-pyrrol-2-yl) acetamide

20 (5-acetyl-1-methyl-1H-pyrrol-2-yl)-N- carboxymethylacetamide

21 (S)(5-acetyl-1-methyl- 1H-pyrrol-2-yl)-N-(2- carboxyethyl)acetamide

22 (5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(3-dimethylaminopropyl)acetamide

23 (S)(5-acetyl-1-methyl-1H-pyrrol- 2-yl)-N-(1-carboxy-2-methoxyethyl)acetamide

24 (4-isobutyl-2-methylphenyl)acetamide

25 (2-chloro-3-propionylphenyl)-N-(3- dimethylaminoethyl)acetamide

26 (3-isopropyl-2-methylphenyl)-N-[3-(1- piperidinyl)propyl]acetamide

27 (3-benzoyl-2-methylphenyl)acetamide

28 (1-benzoyl-2-methyl-1H-indo1-3-yl) acetamide

29 (1-benzoyl-2-methyl-1H-indo1-3-yl)-N-(3-dimethylaminopropyl)acetamide

30 [1-(4-chlorobenzoyl)-2- methyl-1H-indo1-3-yl]acetamide

31 [1-(4-chlorobenzoyl)-5- methoxy-2-methyl-1H-indol-3- yl]acetamide

32 {2-chloro-4-[(trifluoromethanesulfonyl) oxy]phenyl}-N-(2-hydroxyethoxyethyl)acetamide

33 (1-benzoyl-2-methyl- 1H-pyrrol-3-yl)-N-(2- methoxyethyl)acetamide

34 (1-benzoyl-2-chloro-1H- pyrrol-3-yl)-N-[3-(1-morpholino)propyl]acetamide

35 (5-isobutyryl-1-methyl- 1H-pyrrol-2-yl)acetamide

36 (5-benzoyl-1-methyl-1H- pyrrol-2-yl)-N-(2- carboxymethyl)acetamide

37 [1-methyl-5-(4-chlorobenzoyl) 1H-pyrrol-2-yl]-N-(2-hydroxyethoxyethyl)acetamide

38 [1-methyl-5-(4-chlorobenzoyl) 1H-pyrrol-2-yl]acetamide

39 {2-methyl-4-[(phenylsulfonyl) amino)phenyl}-N-(3-dimethylaminopropyl)acetamide

40 (3-benzoyl-2-methoxyphenyl)acetamide

41 (5-acetyl-1-methyl- 1H-pyrrol-2-yl)acetyl methanesulfonamide

42 (4-isobutyl-2-methylphenyl) acetyl methanesulfonamide

43 {2-methyl-4-[trifluoromethanesulfonyl) amino]phenyl} acetylmethanesulfonamide

44 [1-methyl-5-(4-methylbenzoyl)-1H- pyrrol-2-yl]acetylmethanesulfonamide

1-15. (canceled)
 16. A method of treatment of ulcerative colitis,melanoma, chronic obstructive pulmonary disease (COPD), bullouspemphigoid, idiopathic fibrosis, glomerulonephritis and in theprevention and treatment of damages caused by ischemia and reperfusioncomprising administering a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein A is selectedfrom the group consisting of benzene, naphthalene, pyridine, pyrimidine,pyrrole, imidazole, furane, thiophene, indole; labels 1 and 2 mark therelevant positions on the A ring; the X atom is nitrogen or carbon; R isa substituting group on the A ring selected from the group consistingof: a group in the 3 (meta) position that is linear or branchedC₁-C₅-alkyl, linear or branched C₂-C₅-alkenyl, linear or branchedC₂-C₅-alkynyl, or substituted or not-substituted phenyl, linear orbranched C₁-C₅-hydroxyalkyl, C₂-C₅-acyl, substituted or not-substitutedbenzoyl; and a group in the 4 (para) position that is C₁-C₅ alkyl,C₂-C₅-alkenyl, C₂-C₅-alkynyl, C₃-C₆-cycloalkyl, C₁-C₅-acyloxy,substituted or not-substituted benzoyloxy, C₁-C₅-acylamino, substitutedor not-substituted benzoylamino, C₁-C₅-sulfonyloxy, substituted ornot-substituted benzenesulfonyloxy, C₁-C₅-alkanesulfonylamino,substituted or not-substituted benzenesulfonylamino,C₁-C₅-alkanesulfonylmethyl, substituted or not-substitutedbenzenesulfonylmethyl, 2-furyl; 3-tetrahydrofuryl; 2-thiophenyl;2-tetrahydrothiophenyl, C₁-C₈-alkanoyl, cycloalkanoyl orarylalkanoyl-C₁-C₅-alkylamino; Hy is selected from the group consistingof methyl, ethyl, chlorine, bromine, methoxy and trifluoromethyl; andYR′ is OH.
 17. The method according to claim 1, wherein R is 3′-benzoyl,3′-(4-chloro-benzoyl), 3′-(4-methyl-benzoyl), 3′-acetyl, 3′-propionyl,3′-isobutanoyl, 3′-ethyl, 3′-isopropyl, 4′-trifluoromethanesulphonyloxy,4′-benzenesulphonyloxy, trifluoromethanesulphonylamino,4′-benzenesulphonylamino, 4′-benzenesulphonylmethyl, 4′-acetyloxy,4′-propionyloxy, 4′-benzoyloxy, 4′-acetylamino, 4′-propionylamino, or4′-benzoylamino.
 18. The method according to claim 1, wherein thecompound of formula (I) is selected from the group consisting of:(3-benzoyl-2-methylphenyl)acetic acid,(2-chloro-3-propionylphenyl)acetic acid,(3-isopropyl-2-methylphenyl)acetic acid,(4-isobutyl-2-methylphenyl)acetic acid,{2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid,{2-methyl-4-[(trifluoromethanesulphonyl)amino]phenyl}acetic acid,{2-chloro-4-[(trifluoromethanesulphonyl)oxy]phenyl}acetic acid,(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid,[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid,(5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid,[1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]acetic acid,(5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid,(1-benzoyl-2-methyl-1H-pyrrol-3-yl)acetic acid,(1-benzoyl-2-chloro-1H-pyrrol-3-yl)acetic acid,(1-benzoyl-2-methyl-1H-indol-3-yl)acetic acid,[1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetic acid,(1-isopropyl-2-methyl-1H-pyrrole[2,3-b]pyridin-3-yl)acetic acid, and(3-benzoyl-2-methoxyphenyl)acetic acid.